分类： 生物学 >> 生物物理学 提交时间： 2016-05-12
Sun, Xianlei
Gao, Duo
Gao, Liquan
Zhang, Chenran
Yu, Xinhe
Jia, Bing
Wang, Fan
Liu, Zhaofei
Sun, Xianlei
Gao, Duo
Gao, Liquan
Zhang, Chenran
Yu, Xinhe
Jia, Bing
Wang, Fan
Liu, Zhaofei
Wang, Fan
摘要： Significant evidence has indicated that tumor-associated macrophages (TAMs) play a critical role in the proliferation, invasion, angiogenesis, and metastasis of a variety of human carcinomas. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging using a macrophage mannose receptor (MMR; CD206)-targeting agent could be used to noninvasively visualize and quantify changes in TAMs in vivo. The CD206-targeting NIRF agent, Dye-anti-CD206, was prepared and characterized in vitro and in vivo. By using NIRF imaging, we were able to noninvasively image tumor-infiltrating macrophages in the 4T1 mouse breast cancer model. Importantly, longitudinal NIRF imaging revealed the depletion of macrophages in response to zoledronic acid (ZA) treatment. However, ZA alone did not lead to the inhibition of 4T1 tumor growth. We therefore combined anti-macrophage ZA therapy and tumor cytotoxic docetaxel (DTX) therapy in the mouse model. The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs. Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-11
Ma, Teng
Liu, Hao
Sun, Xianlei
Gao, Liquan
Shi, Jiyun
Zhao, Huiyun
Jia, Bing
Wan, Fan
Liu, Zhaofei
Ma, Teng
Liu, Hao
Sun, Xianlei
Gao, Liquan
Jia, Bing
Wan, Fan
Liu, Zhaofei
Shi, Jiyun
Zhao, Huiyun
摘要： Cetuximab is an antiepidermal growth factor receptor (EGFR) monoclonal antibody that has received the approval of the Food and Drug Administration (FDA) for cancer treatment. However, most clinical studies indicate that cetuximab can only elicit positive effects on a subset of cancer patients. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging of tumor vascular endothelial growth factor (VEGF) expression could be a biomarker for tumor early response to cetuximab therapy in preclinical wild-type and mutant tumor models of the KRAS gene. The treatment efficacy of cetuximab was determined in both HT-29 (wild-type KRAS) and HTC-116 (mutant KRAS) human colon cancer models. A VEGF-specific optical imaging probe (Dye755-Ran) was synthesized by conjugating ranibizumab (an anti-VEGF antibody Fab fragment) with a NIRF dye. Serial optical scans with Dye755-Ran were performed in HT-29 and HTC-116 xenograft models. By using longitudinal NIRF imaging, we were able to detect early tumor response on day 3 and day 5 after initiation of cetuximab treatment in the cetuximab-responsive HT-29 tumor model. Enzyme-linked immunosorbent assay (ELISA) confirmed that cetuximab treatment inhibited human VEGF expression in the KRAS wild-type HT-29 tumor but not in the KRAS mutant HCT-116 tumor. We have demonstrated that the antitumor effect of cetuximab can be noninvasively monitored by serial fluorescence imaging using Dye755-Ran. VEGF expression detected by optical imaging could serve as a sensitive biomarker for tumor early response to drugs that directly or indirectly act on VEGF.
分类： 生物学 >> 生物物理学 提交时间： 2016-05-05
Dong, Chengyan
Yang, Sujuan
Zhao, Huiyun
Liu, Zhaofei
Jia, Bing
Wang, Fan
Dong, Chengyan
Yang, Sujuan
Zhao, Huiyun
Liu, Zhaofei
Jia, Bing
Wang, Fan
Dong, Chengyan
Shi, Jiyun
Wang, Fan
Zhao, Huiyun
Zhong, Lijun
Wang, Fan
摘要： We describe herein dual-modality imaging of intraperitoneal colon tumor using an avidin/biotin pretargeting system. A novel dual-modality probe,Tc-99m-HYNIC-lys(Cy5.5)-PEG4-biotin,was designed, synthesized and characterized. Single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and near infrared fluorescence (NIRF) imaging were developed using intraperitoneal LS180 human colon adenocarcinoma xenografts. Following avidin preinjection for 4 hours, 99mTc-HYNIC-lys(Cy5.5)-PEG4-biotin could successfully detect colon tumors of different sizes inside the abdominal region using both modalities, and the imaging results showed no differences. Biodistribution studies demonstrated that the tumors had a very high uptake of the probe (TcHYNIC)-Tc-99m-lys(Cy5.5)-PEG4-biotin(12.74 +/- 1.89% ID/g at 2 h p.i.), and the clearance from blood and other normal tissues occured very fast. The low tumor uptake in the non-pretargeted mice (1.63 +/- 0.50% ID/g at 2 h p.i.) and tumor cell staining results showed excellent tumor binding specificity of the pretargeting system. The ability of the novel probe to show excellent imaging quality with high tumor-to-background contrast, a high degree of binding specificity with tumors and excellent in vivo biodistribution pharmacokinetics should prove that the avidin/biotin based dual-modality pretargeting probe is a promising imaging tool during the entire period of tumor diagnosis and treatment.
分类： 生物学 >> 生物物理学 >> 影像医学与生物医学工程 提交时间： 2016-05-05
Zhang, Chenran
Gao, Liquan
Liu, Hao
Gao, Duo
Lai, Jianhao
Jia, Bing
Wang, Fan
Liu, Zhaofei
Zhang, Chenran
Gao, Liquan
Liu, Hao
Gao, Duo
Lai, Jianhao
Jia, Bing
Wang, Fan
Liu, Zhaofei
Cai, Yuehong
Wang, Fan
摘要： Tumor-associated macrophages (TAMs) play essential roles in tumor invasion and metastasis, and contribute to drug resistance. Clinical evidence suggests that TAM levels are correlated with local tumor relapse, distant metastasis, and poor prognosis in patients. In this study, we synthesized a TAM-targeted probe (IRD-alpha CD206) by conjugating a monoclonal anti-CD206 antibody with a near-infrared phthalocyanine dye. We then investigated the potential application of the IRD-alpha CD206 probe to near-infrared fluorescence (NIRF) imaging and photoimmunotherapy (PIT) of tumors resistant to treatment with the kinase inhibitor sorafenib. Sorafenib treatment had no effect on tumor growth in a 4T1 mouse model of breast cancer, but induced M2 macrophage polarization in tumors. M2 macrophage recruitment by sorafenib-treated 4T1 tumors was noninvasively visualized by in vivo NIRF imaging of IRD-alpha CD206. Small-animal single-photon emission computed tomography (SPECT)/CT and intratumoral micro distribution analysis indicated TAM-specific localization of the IRD-alpha CD206 probe in 4T1 tumors after several rounds of sorafenib treatment. Upon light irradiation, IRD-alpha CD206 suppressed the growth of sorafenib-resistant tumors. In vivo CT imaging and ex vivo histological analysis confirmed the inhibition of lung metastasis in mice by IRD-alpha CD206 PIT. These results demonstrate the utility of the IRD-alpha CD206 probe for TAM-targeted diagnostic imaging and treatment of tumors that are resistant to conventional therapeutics. (C) 2016 Elsevier Ltd. All rights reserved.
分类： 核科学技术 >> 核材料与工艺技术 提交时间： 2023-06-18 合作期刊: 《Nuclear Science and Techniques》
摘要： In recent years, several RGD (Arg-Gly-Asp)-based radiotracers have already been successfully tested in human for the visualization of integrin v3, demonstrating its feasibility in tumor diagnosis. In this paper, we evaluated the 99mTc-3P4-RGD2 single photon emission computed tomography/computerized tomography (SPECT/CT) in patients suffering from space occupying disease of esophagus. 40 patients (34 males and 6 female; mean age: 58.3 years) with a suspected space occupying lesion of esophagus were included, thus finally obtaining their definite pathologic diagnosis (malignant, n=32; benign, n=8). All patients underwent endoscopic, barium esophagography and SPECT/CT imaging preoperatively. The chest SPECT was performed at 4 h after administration of 99mTc-3P4-RGD2 with a dose of 939118 MBq. The diagnosis precision, sensitivity and specificity among these methods were compared. The relationship between radioactive uptake and clinical pathological stage of esophageal carcinoma was discussed by calculating the tumor to normal esophagus (T/N). Meanwhile, the integrin v3 expression was assessed immunohistochemically in postoperative esophageal tissues. 31 patients were diagnosed as esophageal carcinoma; and 1, leiomyosarcoma; and 6. leimyoma; and 2, esophageal tuberculosis. The accuracy, sensitivity and specificity of barium esophagography, endoscopic and SPECT/CT imaging are 92.5/93.8/87.5%, 97.5/96.9/100%, and 90/90.6/87.5%, respectively. Abnormal accumulation of radiotracer in 29 malignant lesions is observed. The SPECT/CT imaging displayed the region of radioactive uptake and lesions matched extremely with the T/N ratio from 1.31 to 2.79 (mean 2.04). A case with pulmonary metastases and a case with mediastinal lymph node metastases were found which were missed by barium esophagography and endoscopic. The 99mTc-3P4-RGD2 uptake of the esophageal carcinoma masses had no relevance to the tumor pathologic classification (P>0.05). There was a significant positive correlation between T/N ratio and positive cell percentage of integrin v3 (r=0.976), demonstrating the certain clinical potential in the diagnosis of esophageal carcinoma.
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